U.S. patent number 4,978,761 [Application Number 07/363,729] was granted by the patent office on 1990-12-18 for 5-hydroxy-2-substituted-2,4,6,7-tetramethyl-2,3-dihydrobenzofurans.
This patent grant is currently assigned to Takeda Chemical Industries, Ltd.. Invention is credited to Naohisa Fukuda, Giichi Goto, Shigenori Ohkawa.
United States Patent |
4,978,761 |
Goto , et al. |
December 18, 1990 |
5-hydroxy-2-substituted-2,4,6,7-tetramethyl-2,3-dihydrobenzofurans
Abstract
The present invention relates to a compound of the formula:
##STR1## wherein R.sup.1 is hydrogen or a lower alkyl; R.sup.2 is
methyl which is substituted by a carboxy, alkoxycarbonyl, cyano,
halogen, aryl or heterocyclic group of C.sub.2-15 chain hydrocarbon
residue having no lower alkyl at the .alpha.-position which may be
substituted by a carboxy, alkoxycarbonyl, cyano, halogen, aryl or
heterocyclic group; R.sup.3 is a lower alkyl; R.sup.4 is hydrogen
or acyl; and R.sup.5 and R.sup.6 each is a lower alkyl or lower
alkoxy, or R.sup.5 and R.sup.6 combinedly are butadienylene or a
salt thereof. The compound (I) of the present invention has a
strong 5- and 12-lipoxygenase inhibiting action, is of high safety
and is useful as, among others, an agent for ameliorating
dysfunction circulatory system, an anti-allergic agent and a
pharmaceutical agent for central nervous system.
Inventors: |
Goto; Giichi (Osaka,
JP), Ohkawa; Shigenori (Osaka, JP), Fukuda;
Naohisa (Kawanishi, JP) |
Assignee: |
Takeda Chemical Industries,
Ltd. (Osaka, JP)
|
Family
ID: |
15348634 |
Appl.
No.: |
07/363,729 |
Filed: |
June 9, 1989 |
Foreign Application Priority Data
|
|
|
|
|
Jun 10, 1988 [JP] |
|
|
63-143859 |
|
Current U.S.
Class: |
549/462; 549/470;
544/153; 548/203; 549/458; 546/284.1; 546/269.7; 546/280.4;
546/272.7; 544/61; 548/311.4 |
Current CPC
Class: |
A61P
37/08 (20180101); A61P 43/00 (20180101); A61P
9/00 (20180101); A61P 37/00 (20180101); C07D
307/79 (20130101); C07D 307/80 (20130101) |
Current International
Class: |
C07D
307/00 (20060101); C07D 307/79 (20060101); C07D
307/80 (20060101); C07D 307/79 () |
Field of
Search: |
;549/458,462,470 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Smith et al., J.A.C.S. 63, pp. 1887-1890 (1941). .
Smith et al., J.S.C.S. 65, pp. 1594-1599 (1943). .
Smith, et al., J. Org. Chem. 6, pp. 229-235 (1941). .
Golumbic, J.A.C.S., 63, p. 1142 (1941). .
Karrer et al., Helvetica Chimica Acta, vol. 31, No. 6, pp.
1505-1513 (1948). .
Yutaka Maruyama et al., "5-Lipoxyggenase Inhibitors for the
Treatment of Inflammation and Allergy", Chemical Abstracts, vol.
108, No. 10, Mar. 7, 1988, p. 445, Abstract No. 82107a. .
Katsuji Ejiri et al., "Dihydrobenzofuran Derivatives as
Antioxidants and drug Intermediates", Chemical Abstracts, vol. 110,
Feb. 27, 1989, p. 630, Abstract No. 75294x. .
CPI Abstract 4854619 WPI Acc. No. 88-145145/21, Abstract of
JP-A-88173/1988. .
Burton, Graham W., et al., "Antioxidant Activity of Phenols Related
to Vitamin E. Are There Chain-Breaking Antioxidants Better Than
.alpha.-Tocopherol?", J. Am. Chem. Soc., vol. 105, pp. 5950-5951
(1983). .
Burton, Graham W., et al., "Autoxidation of Biological Molecules,
4, Maximizing the Antioxidant Activity of Phenols." J. Am. Chem.
Soc., vol. 107, pp. 7053-7065 (1985). .
Okamoto, Kayoko et al., "Synthesis of Quinones having Carboxy- and
Hydroxy-Alkyl Side Chains, and Their Effects on Rat-Liver Lysosomal
Membrane", Chem. Pharm. Bull., vol. 30, No. 8, pp. 2797-2819
(1982). .
Ingold, K. U., et al., "A New Vitamin E Analogue More Active than
.alpha.-Tocopherol in the Rat Curative Myopathy Bioassay", Febs
Letters, vol. 205, No. 1, pp. 117-120 (1986). .
S. Brownstein et al., "Chiral Effects on the 13C Resonances of
Alpha-tocophrol and Related Compounds, A Novel Illustration of
Newman's Rule of Six", Journal of Organic Chemistry, vol. 54, No.
3, Feb. 3, 1989, pp. 560-569..
|
Primary Examiner: Lee; Mary C.
Assistant Examiner: Dentz; Bernard I.
Attorney, Agent or Firm: Wegner, Cantor, Mueller &
Player
Claims
We claim:
1.
5-Hydroxy-2-(phenyl-aliphatic)-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
wherein said aliphatic is C.sub.2-6 alkylene or C.sub.2-6
alkenylene and said phenyl is unsubstituted or substituted by
C.sub.1-3 alkyl, C.sub.1-3 alkoxy or halogen, or a pharmaceutically
acceptable salt thereof.
2. The compound
5-hydroxy-2-cinnamyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran.
3. The compound
5-hydroxy-2-phenylethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran.
Description
This invention relates to 2-substituted coumaran derivatives.
The present inventors synthesized various types of coumaran
derivatives and found that they had inhibitory actions on
5-lipoxygenase and 12-lipoxygenase participating in the
biosynthesis of leucotrienes and lipoxins, and they have continued
the research work diligently to accomplish the present
invention.
The present invention is to provide a compound of the formula:
##STR2## wherein R.sup.1 is hydrogen or a lower alkyl; R.sup.2 is
methyl which is substituted by a carboxy, alkoxycarbonyl, cyano,
halogen, aryl or heterocyclic group or C.sub.2-15 chain hydrocarbon
residue having no lower alkyl at the .alpha.-position which may be
substituted by a carboxy, alkoxycarbonyl, cyano, halogen, aryl or
heterocyclic group; R.sup.3 is a lower alkyl; R.sup.4 is hydrogen
or acyl; R.sup.5 and R.sup.6 each is a lower alkyl or lower alkoxy,
or R.sup.5 and R.sup.6 combinedly are butadienylene, and a salt
thereof.
Referring to compounds represented by the above-mentioned (I), the
lower alkyl represented by R.sup.1 is exemplified by C.sub.1-6
alkyl such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
sec-butyl, t-butyl, amyl, hexyl, etc., especially C.sub.1-3 alkyl
(methyl, ethyl, propyl, i-propyl, etc.) being preferable.
As substituents of the substituted methyl represented by R.sup.2,
mention is made of aryl (phenyl, 1-naphthyl, 2-naphthyl, indanyl,
tetralyl, etc.), heterocyclic group (2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 5-thiazolyl,
morpholino, thiomorpholino, etc), halogen (fluorine, chlorine,
bromine, iodine), carboxyl, alkoxycarbonyl (preferably C.sub.2-5
ones such as methoxycarbonyl, etc.), cyano, etc. Further, the aryl
and the heterocyclic groups may have one or more substituents at an
optional position of the ring. As the said substituents, mention is
made of, for example, unsubstituted C.sub.1-20 alkyl (e.g. methyl,
ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, octyl,
nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, etc.), lower
(C.sub.1-6) alkyl optionally substituted with a hydroxyl group,
carboxyl, C.sub.2-5 alkoxycarbonyl, piperazyl, phenylthio, etc.,
C.sub.2-4 alkenyl (vinyl, etc.) optionally substituted with a
carboxyl or alkoxycarbonyl (C.sub.2-5 alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, etc.), hydroxyl group, halogen
(fluorine, chlorine, bromine, etc.), nitro, formyl, C.sub.1-3
alkoxy (methoxy, etc.), carboxyl, trifluoromethyl, di-C.sub.1-3
alkylamino, C.sub.5-7 cycloalkyl, C.sub.1-3 alkylthio, etc.
As the chain hydrocarbon residue having 2 to 15 carbon atoms, which
has no lower alkyl on the .alpha.-position, represented by R.sup.2,
mention is made of straight-chain or branched C.sub.2-15 chain
aliphatic hydrocarbon groups, and when it is alkenyl, the number of
double bonds is usually 1 to 5, and these double bonds may be
conjugated. And, in the case of alkynyl, the number of its triple
bonds is 1 to 5.
As the above-mentioned chain hydrocarbon residues, those having 2
to 6 carbon atoms are preferable, as exemplified by alkyl such as
ethyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl,
alkenyl and as 1-propenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl,
vinyl 2-propenyl, isopropenyl, and alkynyl such as ethynyl,
2-propynyl, 2-penten-4-ynyl.
Referring to the substituents of C.sub.2-15 chain hydrocarbon
residue represented by R.sup.2, as preferable alkoxycarbonyl,
mention is made of C.sub.2-5 alkoxycarbonyl (methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, i-propoxycarboxyl, etc.), and, as
halogen, mention is made of fluorine, bromine, chlorine and iodine.
For the aryl and heterocyclic groups, reference is made to the
groups described above, and, for further substituents reference is
made to the groups described above.
Examples of the lower alkyl represented by R.sup.3 include
C.sub.1-6 alkyl such as methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, sec-butyl, t-butyl, amyl, hexyl, etc., especially,
C.sub.1-3 alkyls (methyl, ethyl, propyl, i-propyl, etc.) are
preferable.
As the acyl represented by R.sup.4, mention is made of acyl
carboxylate, acyl sulfonate, acyl phosphate, etc., preferably those
having C.sub.1-10 substituents (methyl, ethyl, propyl, phenyl,
etc.). Preferable ones include chain-like (C.sub.1-10) or cyclic
(C.sub.3-10) alkanoyl, such as formyl, acetyl, propionyl,
isobutyryl, decanoyl, cyclopentyl or cyclohexylcarbonyl, benzoyl,
optionally quaterized nicotinoyl, half ester of succinate, etc.
Examples of the lower alkyl represented by R.sup.5 and R.sup.6
respectively include C.sub.1-6 alkyl such as methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, sec-butyl, t-butyl, amyl, hexyl, etc.,
especially preferable ones being C.sub.1-3 alkyl (methyl, ethyl,
propyl, i-propyl, etc.). These substituents are exemplified by
hydroxyl group, halogen (fluorine, bromine, chlorine, iodine,
etc.), nitro, trifluoromethyl, carboxyl, C.sub.2-5 alkoxycarboxyl
(methoxycarbonyl, ethoxycarbonyl, etc.), 3-pyridyl, 1-imidazolyl,
5-thiazolyl, etc. And, examples of the lower alkoxy shown by
R.sup.5 and R.sup.6 include C.sub.1-3 alkoxy such as methoxy,
ethoxy, propoxy, i-propoxy, etc.
When R.sup.5 and R.sup.6 combinedly represent butadienylene, a
naphthalene ring is formed, and as the substituents on the
thus-formed benzene ring, are mentioned one to three lower
(C.sub.1-3) alkyl, lower (C.sub.1-3) alkoxy (methoxy, ethoxy,
propoxy, etc.), hydroxyl groups, nitro, halogen, etc.
The compound (I) may, in accordance with the kinds of substituents
thereon, form corresponding salts, and the salts are exemplified by
those with an organic acid (e.g. acetic acid, propionic acid,
oxalic acid, maleic acid) or an inorganic acid (e.g. hydrochloric
acid, sulfuric acid, phosphoric acid, etc.), or those with a base
such as an alkali metal (potassium, sodium, etc.), an alkaline
earth metal (calcium, magnesium, etc.), ammonia, etc., and, among
them, physiologically acceptable ones are especially
preferable.
The compound (I) can be produced by, for example, allowing a
compound represented by the formula ##STR3## wherein R.sup.1,
R.sup.3, R.sup.5 and R.sup.6 are of the same meaning defined as
above, Z is hydrogen or a hydroxyl-protecting group, to react with
a halogen molecule in the presence of a base to cause ring-closure,
or by subjecting the compound (II) to the treatment with a peracid
in the presence of a base to cause ring closure, followed by
allowing the thus ring-closed compound to react with an oxidizing
agent, then subjecting the thus-obtained compound to an
addition-elimination reaction with a compound represented by the
formula
wherein X is halogen, R.sup.2 is a chain-like hydrocarbon residue
whose carbon number is less by one than that of R.sup.2, followed
by, when desired, subjecting the resultant to deprotection,
acylation, hydrogenation or(and) substituent-exchange reaction,
respectively.
As the hydroxyl-protecting group, C.sub.2-4 alkanoyl such as
acetyl, propionyl, etc. is mentioned.
The ring-closure reaction with the aid of halogen is carried out by
allowing, for example, bromine to react in an organic solvent such
as a halogenated carbon (e.g. chloroform, methylene chloride, etc.)
or acetic acid, etc. at temperatures ranging from -5.degree. C. to
80.degree. C.
And, the cyanation can be carried out, in general, by allowing, for
example, sodium cyanate or potassium cyanate to react in a solvent
such as dimethyl sulfoxide, dimethyl formamide, etc. at
temperatures ranging from 60.degree. C. to 100.degree. C. for 1 to
24 hours. In this case, the protecting group is hydrolyzed with a
small volume of water present in the reaction system to give a
5-hydroxy compound at one stroke.
The ring-closure reaction by the use of a peracid is conducted by
using a peracid such as m-chloroperbenzoic acid in an organic
solvent such as methyl chloride in the presence of a base such as
triethylamine at temperatures ranging from -10.degree. C. to
50.degree. C. And, the oxidation is conducted by using an oxidizing
agent obtained from dimethyl sulfoxide and oxalyl chloride,
chromium trioxide, etc., in an organic solvent such as methylene
chloride, acetone, etc., and, when desired, in the presence of a
base such as triethylamine, etc., at temperatures ranging from
-78.degree. C. to 25.degree. C.
The addition-elimination reaction (Wittig reaction) is conducted by
using, as the base, sodium hydride, sodium hydrobromide, sodium
alcoholate, n-butyl lithium, lithium diisopropyl amide, etc., in a
solvent such as dimethyl sulfoxide, tetrahydrofuran, dimethoxy
ethane, etc. at temperatures ranging from -78.degree. C. to
80.degree. C. for about 0.5 to 24 hours.
And, when the double bond is hydrogenated, the object compound can
be obtained in accordance with a conventional method using a
catalyst such as palladium-carbon, etc.
The elimination (hydrolysis) of the hydroxy-protecting group can be
conducted under the conditions of conventional ester hydrolysis,
but, when the product is unstable against oxygen under basic
conditions, the reaction is conducted under argon atmosphere to
thereby obtain the desired hydrolyzate in a good yield.
The acylation is carried out by using a desired acylating agent
(acid anhydride, acid halogenide, etc.), when necessary, in the
presence of a basic catalyst (preferably sodium hydride, potassium
carbonate, pyridine and triethylamine) or an acid catalyst
(sulfuric acid, hydrogen chloride, etc.), in an organic solvent
(e.g. dimethylformamide, acetone, tetrahydrofuran) at temperatures
ranging from about -10.degree. C. to 100.degree. C. for about 10
minutes to 15 hours.
The compound thus obtained (I) can be isolated by conventional
separation purification means (extraction, chromatography,
recrystallization, etc.).
And, when the compound (I) exists in the state of a diastereomer,
the respective components can be isolated by the above-mentioned
separation purification means.
And, when the compound (I) is an optically active compound, it can
be resolved into the d-compound and l-compound by conventional
means for optical resolution.
The starting compound (II) can be synthesized by, for example, the
method described below. More specifically, the monoacetate (IV) of
hydroquinone is allowed to react with aryl halogenide in the
presence of a base to lead to allyl ether (V), followed by
subjecting (V) to Claisen rearrangement to give (II). ##STR4##
The compound (I) of this invention has an action of inhibiting
production of 5-lipoxygenase-type metabolites [leucotrienes,
5-hydroperoxyeicosatetraenoic acid (HPETE),
5-hydroxyeicosatetraenoic acid (HETE), lipoxins, leucotoxins, etc.]
and 12-lipoxygenase-type metabolites (12-HPETE, 12-HETE, etc.),
and, therefore, the compound (I) can be used advantageously as an
agent for ameliorating dysfunction of the circulatory system, an
anti-allergic agent, and an agent acting on the central nervous
system.
The compound (I) can be safely administered, orally or parenterally
singly or as a pharmaceutical composition prepared by mixing the
compound (I) with a per se known pharmaceutically acceptable
carrier, excipient, etc. (e.g. tablet, capsule, liquid, injection,
suppository), to mammals (rat, horse, cow, monkey, human, etc.).
While the dosage varies with subjects of administration,
administration routes, symptoms, etc., in the case of, for example,
administering orally to an adult patient suffering from diseases of
circulatory system, it is convenient to administer about 0.1 mg/kg
to 20 mg/kg/body weight/dose, preferably 0.2 mg/kg to 10 mg/kg/body
weight, once to three times a day.
Experimental Example 1:5-Lypoxygenase Inhibiting Action
In 0.5 ml of MCM (mast cell medium) was suspended 10.sup.7 of rat
basophilic leukemia (RBL-1) cells. To this suspension was added the
test solution previously prepared [consisting of 0.5 ml of MCM, 50
.mu.g of arachidonic acid, 10 .mu.g of calcium ionophore A-23187
and the test compound (final concentrations 10 .mu.m, 1 .mu.m, 0.1
.mu.m and 0.01 .mu.m)], and the reaction was allowed to proceed at
37.degree. C. for 20 minutes. To the reaction mixture was added 4
ml of ethanol, which was shaken sufficiently, followed by leaving
the resultant mixture standing for 10 minutes at room temperatures.
The resultant mixture was subjected to a centrifuge (2000 rpm) for
10 minutes, then the supernatant was separated. Thus-separated
supernatant was concentrated to dryness under reduced pressure. To
the concentrate was added 0.5 ml of a 60% aqueous methanol. A
100.mu.l Portion of this solution was taken and subjected to high
performance liquid chromatography to perform quantitative
determination of 5-HETE (5-hydroxyeicosatetraenoic acid). UV
absorption of 5-HETE at 237 nm was measured with a UV absorption
monitor. The inhibitory effect (IE) of 5-HETE is expressed by
(1-b/a).times.100. In this formula, a means the height of the peak
or the area of the peak in the case of presence of no compound (I),
while b means the height of the peak or the area of the peak in the
case of presence of the compound (I). The results revealed, as
shown in Table 1, that the test compounds showed strong inhibitory
action on the production of 5-HETE.
TABLE 1 ______________________________________ Effect of Inhibiting
5-Lipoxygenase % Inhibition (IE) Compound 10.sup.-5 M 10.sup.-6 M
10.sup.-7 M 10.sup.-8 M ______________________________________ 5
100 100 57 0 6 100 100 52 4 10 100 99 98 12 12 100 100 90 46
______________________________________
Experimental Example 2
Through the descending aorta of a Wistar rat, 10 ml of blood was
collected, under anesthesia, together with citric acid of a volume
corresponding to 10%. PRP and PPP were respectively prepared, then
they were mixed to make the number of platelets to be 10.sup.9 /ml.
To 2.5 .mu.l each of the test solutions prepared in advance (final
concentrations of the test compounds : 100 .mu.m, 10 .mu.m, 1 .mu.m
and 0.1 .mu.m) was added 0.225 ml of the platelet solution. The
respective solutions were kept at 37.degree. C. for 5 minutes, to
which was added 25 .mu.l each of arachidonic acid solution (50
.mu.g/ml) , then the respective mixtures were shaken immediately.
The reaction was allowed to proceed at 37.degree. C. for 15
minutes, and there was added ethanol (1 ml) to stop the reaction.
The reaction mixture was subjected to a centrifuge (2000 rpm) for 5
minutes. One ml of the supernatant was taken, which was mixed with
1 ml of water. 100 .mu.l of this mixture solution was subjected to
high performance liquid chromatography to quantitatively determine
12-HETE. The detection was conducted at 240 nm. The calculation of
the inhibition rate was conducted in a manner as in the case of
5-HETE. The results were shown in Table 2.
TABLE 2 ______________________________________ 12-Lipoxygenase
Inhibitory Action % Inhibition (IE) Compound 10.sup.-4 M 10.sup.-5
M 10.sup.-6 M 10.sup.-7 M ______________________________________ 5
97 78 14 -- 6 98 88 16 2 10 96 92 52 45 12 95 82 11 -- 15 100 100
99 25 17 100 99 98 22 18 100 100 89 18 20 100 99 97 9 21 100 100 98
21 23 100 100 92 19 24 100 99 98 13 26 100 99 28 -- 27 100 100 99
19 29 100 99 58 7 30 100 100 98 21 32 99 99 45 2 33 100 100 28 2 35
99 99 49 8 36 100 100 100 97 37 100 100 31 2 38 99 99 90 3 39 100
100 32 -- 40 99 96 48 6 41 99 74 20 9
______________________________________
EXAMPLES
By the following Reference Examples, Examples and Formulation
Examples of the compounds of the present invention, the present
invention will be described in a more concrete manner, but the
present invention is not to be limited thereto.
REFERENCE EXAMPLE 1
To a solution of 4-acetoxy-2,3,5-trimethylphenol [20 g (103 mmol )]
and methallyl chloride [10 g (110.4 mmol.)] in dimethylformamide
(160 ml) was added potassium carbonate [15.2 g (110 mmol.)]. The
mixture was stirred for 3 hours at 80.degree. C. under argon
atmosphere. The reaction mixture was, after cooling, diluted with
water, and subjected to extraction with ethyl acetate. The extract
was washed with water and dried, then the solvent was distilled
off. The residue was crystallized from hexane to obtain the desired
4-acetoxy-2,3,5-trimethylphenyl-2-methylpropenylether [18.5 g
(yield 72.4%)], m.p.44.degree. to 45.degree. C.
In a manner as above, 4-acetoxy-2,3,5-trimethylphenyl allyl ether
was synthesized. (yield 76.7%, m.p. 40.degree.-41.degree. C.).
REFERENCE EXAMPLE 2
In N,N-diethylaniline (100 ml) was dissolved
4-acetoxy-2,3,5-trimethylphenyl 2-methylpropenylether [16.2 g (6.5
mmol)], which was heated at 200.degree. C. for two hours. The
reaction mixture was cooled and diluted with isopropyl ether, which
was washed with 2N-HCl to remove N,N-diethylaniline. The remainder
was washed with a saturated aqueous solution of sodium
hydrogencarbonate, which was dried, followed by distilling off the
solvent. The residue was crystallized from isopropylether-hexane to
obtain the desired
4-acetoxy-2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol [14.9 g
(yield 91.7%)], m.p. 109.degree.-110.degree. C.
In a manner similar to the above,
4-acetoxy-2-allyl-3,4,6-trimethylphenol was synthesized. (Yield
94.6%, m.p. 117.degree.-118.degree. C.)
REFERENCE EXAMPLE 3
In methylene chloride (100 ml) was dissolved
4-acetoxy-2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol [30 g (40.3
mmol)]. To the solution was added at 0.degree. C., in limited
amounts, m-chloroperbenzoic acid [16.7 g (67.8 mmol)]. The reaction
mixture was stirred for one hour, and there was added triethylamine
(30 ml), followed by stirring for further one hour. The reaction
mixture was washed with a saturated aqueous solution of sodium
hydrogen carbonate, and then dried, followed by distilling off the
solvent. The residue was crystallized from isopropyl ether-hexane
to obtain the desired
5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
[9.3 g (yield 87.4%, m.p. 98.degree.-99.degree. C.)].
REFERENCE EXAMPLE 4
To a methylene chloride solution (50 ml) of oxalyl chloride (2 ml)
was added dropwise at -60.degree. C. dimethylsulfoxide (4 ml). The
mixture was stirred for 10 minutes, and there was then added
dropwise a methylene chloride solution (10 ml) of
5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
[5.0 g (19 mmol)]. The reaction mixture was stirred for 15 minutes,
and there was added triethylamine (15 ml), and the mixture was
stirred for further 10 minutes. The reaction mixture was washed
with water and dried, followed by distilling off the solvent. The
residue was crystallized from isopropylether-hexane to obtain
5-acetoxy-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (yield
96.7%), m.p. 78.degree.-79.degree. C.
EXAMPLE 1
To a chloroform (15 ml) solution of
4-acetoxy-2-allyl-3,5,6-trimethylphenol [2.0 g(8.5 mmol)] was added
dropwise, while stirring, bromine [1.36 g (8.5 mmol)]. To the
mixture was then added triethylamine (0.3 ml), which was heated for
two hours under reflux. The reaction mixture was cooled, washed
with water, dried and then concentrated. The concentrate was
crystallized from hexane to obtain
5-acetoxy-2-bromoethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran
(Compound 14) [2.5 g(yield 93.2%)].
In a manner as above,
5-acetoxy-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
(Compound 13) was obtained from
4-acetoxy-3,5,6-trimethyl-2-(2-methyl-2-propenyl)phenol.
EXAMPLE 2
To a dimethyl sulfoxide (5 ml) solution of
5-acetoxy-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
[1.5 g(4.58 mmol)] was added sodium cyanide [270 mg (5.5 mmol)],
and the mixture was stirred at 80.degree. C. for 6 hours under
argon atmosphere. The reaction mixture was, after cooling, diluted
with water, and subjected to extraction with ethyl acetate. The
extract was washed with water and dried, followed by distilling off
the solvent. The residue was purified by means of a silica gel
column chromatography [hexane - isopropyl ether (2:1)] to obtain
5-acetoxy-2,3-dihydrobenzofuran (Compound 6) (350 mg) and
5-acetoxy-2-cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
(Compound 5)(158 mg).
EXAMPLE 3
To a dimethylformamide (20 mol) solution of triethyl
phosphonoacetate [2.7 g (12.1 mmol)] was added sodium hydride
(content 60%)(504 mg), which was stirred for 15 minutes. To the
reaction mixture was added a dimethyl formamide (5 ml) solution of
5-acetoxy-2-formyl-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran [3.0 g
(11.5 mmol)], and the mixture was stirred for further 30 minutes.
The reaction mixture was diluted with water, and subjected to
extraction with ethyl acetate. The extract solution was washed with
water and dried, followed by distilling off the solvent. The
residue was crystallized from hexane-isopropylether to obtain
3-(5-acetoxy-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-2-yl)acetic
acid ethyl ester (Compound 4)(3.5 g). In a manner as above,
Compound 8 was synthesized.
EXAMPLE 4
To a methanol (10 ml) solution of the ethyl ester of
3-(5-acetoxy-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-2-yl)
acrylic acid [3.5 g (10.5 mmol)] was added a solution of sodium
hydroxide (1.0 g) in water (5 ml). The mixture was heated for two
hours under reflux under argon atmosphere. The reaction mixture was
cooled and neutralized with 2N-HCl, and then subjected to
extraction with isopropyl ether. The extract solution was washed
with water and dried, followed by distilling off the solvent. The
residue was crystallized from tetrahydrofuran - ethyl acetate to
afford the desired
3-(5-acetoxy-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-2-yl)acrylic
acid (Compound 3)(2.06 g). In a manner as above, Compounds 7 and 10
were synthesized.
EXAMPLE 5
To a solution of
3-(5-acetoxy-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-2-yl)acrylic
acid (1.0 g) in acetic acid (10 ml) was added 5% palladium-carbon
(0.4 g), and the mixture was subjected to hydrogenation for two
hours at 80 C. The catalyst was then filtered off, which was
followed by distilling off the solvent. The residue was
crystallized from tetrahydrofuran-isopropyl ether (IPE) to afford
the desired
3-(5-hydroxy-2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-2-yl)
propionic acid (Compound 2)(0.97 g). In a manner as above,
Compounds 9 and 12 were obtained.
EXAMPLE 6
To a solution of
5-hydroxy-2-cyanomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
in methanol (5 ml) was added a solution of sodium hydroxide (0.5 g)
in water (5 ml). The mixture was heated for three hours under
reflux under argon atmosphere. The reaction mixture was cooled to
0.degree. C. neutralized with 2N-HCl. The reaction product was
extracted with ethyl acetate. The extract solution was washed with
water, dried and concentrated, and then crystallized from ethyl
acetate - isopropyl ether to afford the desired
2-(5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl)acetic
acid (Compound 1) (0.1 g).
EXAMPLE 7
To a suspension of benzyltriphenyl phosphonium chloride [1.5 g
(3.87 mmol)] in tetrahydrofuran (5 ml) was added dropwise, under
ice-cooling, an n-butyl lithium hexane solution [(1.6M) 24 ml],
followed by stirring for 15 minutes. To the reaction mixture was
added a solution of
5-acetoxy-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (1.0
g) in tetrahydrofuran (3 ml). To the mixture was added water and it
was subjected to extraction with ethyl acetate. The extract
solution was washed with water and dried, then the solvent was
distilled off. The residue was purified by means of a silica gel
column chromatography [hexane-IPE(2:1)] to obtain the desired
5-acetoxy-2-cinnamoyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran
(Compound 11) (1.22 g).
Physico-chemical properties of the compounds obtained as above are
shown in Table 3.
TABLE 3
__________________________________________________________________________
##STR5## Compd. Yield m.p. No. R.sup.1 R.sup.2 R.sup.4 (%)
(.degree.C.) NMR(.delta. ppm) CDCl.sub.3 .phi.
__________________________________________________________________________
1 Me CH.sub.2 CO.sub.2 H H 22.7 184-185 1.47(3H), 1.98(3H),
2.03(6H), 2.63(2H), 2.80(1H), 3.20(1H), 4.00(1H), 7.10(1H); in
DMSO-d.sub.6 2 Me (CH.sub.2).sub.2 CO.sub.2 H H 96.3 164-165
1.33(3H), 1.85(2H), 1.97(3H), 2.03(6H), 2.27(2H), 2.73(1H),
2.95(1H), 3.50(1H), 7.20(1H); in DMSO-d.sub.6 3 Me ##STR6## H 74.6
211-212 1.53(3H), 2.05(6H), 3.03(2H), 3.60(1H), 5.83(1H), 6.92(1H),
7.10(1H); in DMSO-d.sub.6 4 Me ##STR7## Ac 92.0 91-92 1.27(3H),
1.58(3H), 1.95(3H), 2.00(3H), 2.13(3H), 2.30(3H), 3.07(2H),
4.17(2H), 6.02(1H), 7.05(1H) 5 Me CH.sub.2 CN H 11.7 127-128
1.63(3H), 2.10(6H), 2.68(2H), 2.95(1H), 3.17(1H), 4.20(1H) 6 Me
CH.sub.2 Br H 26.8 101-102 1.60(3H), 2.12(9H), 2.88(1H), 3.27(1H),
3.48(2H), 4.15(1H) 7 Me ##STR8## H 82.9 204-206 1.50(3H), 2.03(9H),
3.00(2H), 3.90(1H), 5.87(1H), 6.37(2H), 7.15(1H); in DMSO-d.sub.6 8
Me ##STR9## Ac 87.8 -- 1.27(3H), 1.57(3H), 1.97(3H), 2.03(3H),
2.13(3H), 2.33(3H), 3.05(2H), 4.17(2H), 5.87(1H), 6.37(2H),
7.20(1H) 9 Me (CH.sub.2).sub.4 CO.sub.2 H H 74.0 143-144 1.28(3H),
1.50(6H), 1.93(3H), 2.00(6H), 2.20(2H), 2.72(1H), 2.93(1H),
7.20(1H); in DMSO-d.sub.6 10 Me ##STR10## H 95.1 -- 1.52(3H),
1.87(3H), 2.00(3H), 2.07(3H), 2.88(1H), 3.18(1H), 4.08(1H),
5.90(1H), 6.48(1H), 7.23(5H) 11 Me ##STR11## Ac 95.2 -- 1.57(3H),
1.90(6H), 1.97(3H), 2.30(3H), 2.88(1H), 3.20(1H), 5.90(1H),
6.50(1H), 7.25(5H) 12 Me (CH.sub.2).sub.2Ph H 85.7 80-81 1.47(3H),
1.98(2H), 2.13(6H), 2.15(3H), 2.73(2H), 2.87(1H), 3.05(1H),
4.08(1H), 7.23(5H) 13 Me CH.sub.2 Br Ac 91.0 -- 1.60(3H), 2.00(6H),
2.10(3H), 2.30(3H), 2.90(1H), 3.30(1H), 3.50(2H) 14 H CH.sub.2 Br
Ac 93.2 80-81 2.00(6H) 2.10(3H), 2.30(3H), 3.13(2H), 3.53(2H),
4.97(1H) 15 Me ##STR12## H 70.4 62-63 1.57(3H), 2.11(3H), 2.16(3H),
2.18(3H), 3.06(1H), 3.20(1H), 3.56(1H), 3.69(1H), 4.16(1H),
5.56(1H), 5.75(1H), 7.15-7.35(5H) 16 Me ##STR13## Ac 74.9 oil
1.60(3H), 2.00(6H), 2.08(3H), 2.32(3H), 3.05(1H), 3.23(1H),
3.56(1H), 3.67(1H), 5.50(1H), 5.75(1H), 7.23(5H,m) 17 Me ##STR14##
H 50.0 97- 98 1.52(3H), 2.10(3H), 2.12(3H), 2.14(3H), 2.95(1H),
3.10(1H), 3.38(2H), 4.15(1H), 5.74(1H), 5.84(1H), 7.10-7.40(5H,m)
18 Me ##STR15## H 61.0 107-108 1.64(3H), 2.11(3H), 2.16(3H),
2.18(3H), 3.06(1H), 3.20(1H), 4.17(1H), 6.40(1H), 6.64(1H),
7.15-7.45(5H) 19 Me ##STR16## Ac 92.0 103-105 1.63(3H), 1.97(3H),
2.02(3H), 2.15(3H), 2.30(3H), 3.00(1H), 3.23(1H), 6.33(1H),
6.65(1H), 7.20-7.50(5H) 20 Me (CH .sub.2).sub.3Ph H 93.3 92-93
1.37(3H), 1.72(4H), 2.07(6H), 2.10(3H), 2.62(2H), 2.77(1H),
2.97(1H), 4.07(1H), 7.00-7.35(5H) 21 Me ##STR17## H 95.5 64-65
1.45(3H), 2.07(6H), 2.12(3H), 2.61(4H), 3.00(2H), 4.08(1H),
5.48(1H), 6.14(1H), 7.00-7.30(5H) 22 Me ##STR18## Ac 57.6 oil
1.47(3H), 1.93(3H), 1.98(3H), 2.07(3H), 2.30(3H), 2.40-2.80(2H),
3.00(2H), 5.38(1H), 5.68(1H), 7.00-7.35(5H) 23 Me
(CH.sub.2).sub.4Ph H 87.5 73-74 1.20-1.80(6H), 1.03(3H), 1.07(6H),
2.12(3H), 2.60(2H), 2.77(1H), 2.97(1H), 4.08(1H),7.00-7.35(5H) 24
Me ##STR19## H 97.0 oil 1.53(3H), 1.93(3H), 2.02(3H), 2.08(3H),
2.90(1H), 3.22(1H), 3.78(3H), 4.17(1H), 5.83(1H), 6.42(1H),
6.78(2H), 7.23(2H) 25 Me ##STR20## Ac 81.1 oil 1.53(3H), 1.92(6H),
1.97(3H), 2.27(3H), 2.90(1H), 3.22(1H), 3.77(3H), 5.83(1H),
6.42(1H), 6.77(2H), 7.20(2H) 26 Me (CH.sub.2).sub.2Ph-4-OMe H 93.8
77-78 1.47(3H), 1.65-2.10(2H), 2.13(6H), 2.15(3H), 2.40-2.80(2H),
2.83(1H), 3.05(1H), 3.78(3H), 4.10(1H), 6.78(2H), 7.10(2H) 27 Me
##STR21## H 98.0 oil 1.53(3H), 1.90(3H), 2.02(3H), 2.08(3H),
2.90(1H), 3.22(1H), 3.67(3H), 4.17(1H), 5.90(1H), 6.48(1H),
6.65-7.30(4H) 28 Me ##STR22## Ac 92.6 oil 1.53(3H), 1.88(6H),
1.95(3H), 2.90(1H), 3.23(1H), 3.67(3H), 5.88(1H), 6.47(1H),
6.60-6.90(3H), 7.05-7.30(1H) 29 Me (CH.sub.2).sub.2Ph-3-OMe H 84.2
79-80 1.47(3H), 1.70-2.10(2H), 2.10(6H), 2.13 (3H), 2.40-2.80(2H),
2.83(1H), 3.05 (1H), 3.77(3H), 4.10(1H), 6.60-6.85(3H)
7.10-7.30(1H) 30 Me ##STR23## H 94.6 oil 1.53(3H), 1.85(3H),
2.03(3H), 2.07(3H), 2.90(1H), 3.20(1H), 4.20(1H), 5.85(1H),
6.43(1H), 6.75-7.10(2H), 7.10-7.30(2H) 31 Me ##STR24## Ac 88.8 oil
1.55(3H), 1.83(3H), 1.90(3H), 1.93(3H), 2.27(3H), 2.90(1H),
3.22(1H), 5.87(1H), 6.42(1H), 6.90(2H), 7.20(2H) 32 Me
(CH.sub.2).sub.2Ph-4-F H 79.6 76-77 1.47(3H), 1.70-2.10(2H),
2.10(6H), 2.13 (3H), 2.40-2.80(2H), 2.83(1H), 3.05(1H) 4.10(1H),
7.10(4H) 33 Me ##STR25## H 96.5 oil 1.53(3H), 1.90(6H), 1.97(3H),
2.28(3H), 2.33(3H), 2.90(1H), 3.22(1H), 5.87(1H), 6.47(1H),
6.95-7.25(4H) 34 Me ##STR26## Ac 91.1 oil 1.53(3H), 1.90(3H),
2.00(3H), 2.07(3H), 2.88(1H), 3.20(1H), 4.10(1H), 5.87(1H),
6.43(1H), 6.90-7.30(4H) 35 Me (CH.sub.2).sub.2Ph-4-Me H 80.5
106-107 1.47(3H), 1.70-2.10(2H), 2.10(6H), 2.13(3H), 2.40-2.80(2H),
2.83(1H), 3.05(1H), 4.10(1H), 7.10(4H) 36 Me ##STR27## H 41.5 oil
0.91(3H), 1.40(2H), 1.52(3H), 2.12(6H), 2.17(3H), 2.19(2H),
3.04(2H), 3.16(1H), 4.16(1H), 5.38(1H), 5.68(1H) 37 Me
(CH.sub.2).sub.4 Me H 90.4 59-60 0.88(3H), 1.29(6H), 1.39(3H),
1.68(6H), 2.10(6H), 2.13(3H), 2.81(1H), 2.97(1H), 4.14(1H) 38 Me
##STR28## H 49.7 oil 0.88(3H), 1.26(10H), 1.51(3H), 2.12(6H),
2.14(3H), 2.20(2H), 3.04(2H), 3.16(1H), 4.15(1H), 5.38(1H),
5.66(1H) 39 Me (CH.sub.2).sub.8 Me H 83.3 69-70 0.88(3H),
1.26(14H), 1.39(3H), 1.70 (2H), 2.10(6H), 2.13(3H), 2.81(1H),
2.97(1H), 4.13(1H) 40 Me ##STR29## H 45.8 oil 0.88(3H), 1.25(18H),
1.51(3H), 2.11 (6H), 2.14(3H), 2.20(2H), 3.04(2H), 3.16(1H),
4.14(1H), 5.38(1H), 5.66(1H) 41 Me (CH.sub.2).sub.12 Me H 84.6
67-68 0.88(3H), 1.25(22H), 1.39(3H), 1.68 (2H), 2.10(6H), 2.13(3H),
2.81(1H), 2.97(1H), 4.14(1H)
__________________________________________________________________________
Me: Methyl, Ac: Acetyl, Ph: Phenyl
Formulation Examples
______________________________________ (A) Soft capsule
______________________________________ (1) Compound 3 50 mg (2)
Corn oil 100 mg total 150 mg
______________________________________
By a conventional method, (1) and (2) were mixed, which was filled
in a capsule.
(B) Tablet
______________________________________ (B) Tablet
______________________________________ (1) Compound 10 50 mg (2)
Lactose 30 mg (3) Corn starch 10.6 mg (4) Corn starch (paste) 5 mg
(5) Magnesium stearate 0.4 mg (6) Carboxymethyl cellulose sodium 20
mg total 120 mg ______________________________________
By a conventional method, these were mixed, which are tableted by a
tablet machine.
* * * * *